• Immunosuppression;
  • kidney transplant;
  • prospective;
  • śteroid-free


  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

We compared three maintenance immunosuppressive regimens in a rapid discontinuation of prednisone protocol. From March 1, 2001, through December 31, 2003, 239 first and second kidney transplant recipients (166 LD; 73 DD) were randomized. All recipients were treated with Thymoglobulin; all received steroids intraoperatively and for 5 days postoperatively. Randomization was to cyclosporine–mycophenolate mofetil (n = 85); high-level tacrolimus (TAC) (8–12 ng/mL)–low-level sirolimus (SRL) (3–7 ng/mL) (n = 72); or low-level TAC (3–7 ng/mL)–high-level SRL (8–12 ng/mL) (n = 82). We found no difference at 24 months between groups in patient, graft, death-censored graft, or acute rejection-free graft survival, or in kidney function.

Wound complications were more common in SRL-treated recipients (p = 0.02); we found no other differences between groups in complication rates. Our data suggest that excellent patient and graft survival and low rejection rates can be obtained using a variety of maintenance protocols without prednisone.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Long-term prednisone use in kidney transplant recipients is associated with numerous side effects, including hypertension, diabetes, loss of bone mineral density, fractures, and skin and appearance changes (1–3). Importantly, numerous studies have shown that immunosuppression-related side effects are associated with recipient noncompliance (4), which, in turn, is associated with an increased risk of rejection, graft dysfunction, and graft loss (5). Thus, there are compelling reasons to consider prednisone-free immunosuppressive regimens.

Unfortunately, most studies of late (≥3 months posttransplant) prednisone withdrawal have demonstrated increased acute rejection rates after the prednisone was stopped (6–10). More recently, we and others have shown that acute rejection rates are not increased if prednisone is completely avoided, or if it is stopped in the first few posttransplant days (11–22). Furthermore, the prednisone-free recipients had decreased complication rates and improved compliance (22,23).

A number of concerns remain about prednisone-free regimens. First, prednisone is an anti-inflammatory drug, and may play a role in preventing chronic graft changes. Of note, a Canadian prospective, randomized, multicenter trial of prednisone withdrawal at 3 months posttransplant showed no differences between the prednisone withdrawal and maintenance groups for 500–600 days; however, significantly more graft loss occurred in the withdrawal group after 600 days (6). Thus, concern persists that, even with no increase in early rejection rates in prednisone-free maintenance regimens, chronic graft loss might increase. Second, it is unknown whether or not an ideal maintenance immunosuppressive regimen exists for prednisone-free kidney recipients. Our current study was designed to address both of those concerns.

In our early trials of prednisone-free immunosuppression, maintenance therapy consisted of cyclosporine (CSA) and mycophenolate mofetil (MMF). Then, considerable data began to emerge indicating that sirolimus (SRL) could minimize long-term fibrosis by inhibiting smooth muscle proliferation (24–26) and intimal thickening in blood vessels (24,27–29); in fact, SRL was incorporated into coronary artery stents to decrease late recurrence of intimal thickening (24,30). We questioned whether this specific property of SRL would be of long-term benefit in a prednisone-free regimen, and whether SRL would minimize the late graft dysfunction that was seen in the Canadian study (16) of late steroid withdrawal.

When we designed our current study, we contemplated a randomized comparison of CSA–MMF (our routine maintenance therapy at that time) vs. CSA–SRL; but then data emerged indicating that CSA–SRL (used in full doses) was associated with increased 1-year serum creatinine levels (31,32). Therefore, we decided to compare CSA–MMF vs. tacrolimus (TAC)–SRL. Because the combination of TAC–SRL had not been previously used, we created a three-arm study including a group targeted to high TAC and low SRL levels and a group targeted to low TAC and high SRL levels. The primary endpoint of our study is long-term (i.e. at 7 years posttransplant) graft outcome. We herein present an interim analysis of our rates of graft and patient survival, acute rejection, and complications.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Beginning on March 1, 2001, all recipients of first and second kidney transplants (with either a living or deceased donor) at our institution were invited to participate in this randomized study of prednisone-free maintenance immunosuppression. In addition, for a brief time, recipients of first simultaneous kidney–pancreas transplants were invited to participate (but, thereafter, a different study protocol was given priority). Our protocol was approved by the University of Minnesota Human Subjects Committee. The only exclusion criterion for study entry was taking maintenance prednisone within 3 months pretransplant. Recipients eligible for prednisone-free maintenance immunosuppression who chose not to participate in this randomized study received our standard prednisone-free maintenance therapy (CSA–MMF).

The protocol for our three-arm study is outlined in Figure 1. The primary endpoint is the composite of return to dialysis, death with function, retransplant, and biopsy-proven chronic allograft nephropathy at 7 years posttransplant. To ensure that we do not miss a 15% difference between groups in our primary endpoint (power = 0.8), we require 150 recipients per arm.


Figure 1. Outline of randomized study.

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From March 1, 2001, through December 31, 2003, a total of 239 kidney transplant recipients were randomized (by card pull) to one of the three maintenance therapy arms (Table 1): (1) CSA–MMF (n = 85), (2) high (blood level) TAC–low (blood level) SRL (n = 72), and (3) low (blood level) TAC–high (blood level) SRL (n = 82). For both TAC and SRL, high blood level was defined as 8–12 mg/mL and low blood level as 3–7 mg/mL.

Table 1.  Recipient characteristics
  CSA–MMF (n = 85)High TAC– Low SRL (n = 72)Low TAC– High SRL (n = 82)
  1. HLA = human leukocyte antigen, SPK = simultaneous pancreas–kidney, PRA = panel-reactive antibody, Tx = transplant, SD = standard deviation.

Transplant type
 Kidney (%)989896
 SPK (%)222
Donor source
 Deceased donor (%)312735
 HLA-identical (%)758
 Living unrelated (%)212726
Primary disease
 Diabetes-type 1 (%)262729
 Diabetes-type 2 (%)11913
 Polycystic (%)111313
 Hypertension (%)774
 Male (%)616068
 Female (%)394032
 White (%)929396
 African American (%)420
 Native American (%)221
 Asian American (%)111
Recipient weight (kg)
 Mean ± SD Pretx75 ± 1778 ± 2180 ± 19
Transplant #
 First (%)949590
 Second (%)6510
 Mean age (years) ± SD49 ± 1447 ± 1348 ± 13
 Mean HLA mismatch ± SD3.1 ± 1.93.1 ± 1.93.2 ± 1.9
 Peak PRA > 10% (%)211111
 Tx PRA > 10% (%)1478

All recipients received Thymoglobulin (Genzyme Corporation, Boston, MA) at a dose of 1.25–1.5 mg/kg intravenously (IV) for five doses, with the first dose given intraoperatively. If delayed graft function (DGF) occurred, additional doses (up to a maximum of 10 doses) were given. The Thymoglobulin dose was cut in half for a platelet count of 50 000–90 000/mm3, or a white blood count of 2000–3000/mm3, or an absolute lymphocyte count (ALC) of 100–200/mm3; it was held for a platelet count of <50 000/mm3, or a white blood count of <2000/mm3, or an ALC of <100/mm3. All recipients received methylprednisolone (500 mg) intraoperatively. Prednisone was given at 1 mg/kg on posttransplant day 1; 0.5 mg/kg on days 2 and 3; and 0.25 mg/kg on days 4 and 5. After day 5, prednisone was discontinued, except in recipients with DGF (they were given 5 mg/day of prednisone until Thymoglobulin treatment was discontinued; at that point, their prednisone was also stopped).

For the CSA–MMF arm, MMF (1 g IV) was given intraoperatively. Oral MMF (1 g bid for non-African Americans; 1.5 g bid for African Americans) was started on posttransplant day 1. The MMF dose was adjusted for gastrointestinal side effects (nausea, vomiting, or diarrhea) or bone marrow suppression. Management of leukopenia has been described in detail previously (21). CSA was started at 8 mg/kg/day (in two divided doses) and adjusted to achieve levels of 150–200 μg/L (by high-performance liquid chromatography [HPLC]) for the first 3 months. CSA was delayed, or gradually introduced, in recipients with slow graft function or DGF.

For the high TAC–low SRL arm, 1 mg of SRL was given preoperatively. Postoperatively, SRL (2 mg/day) was started. The dose was adjusted to achieve levels of 3–7 μg/L (by HPLC). TAC was started postoperatively at 0.06 mg/kg; the dose was adjusted to achieve levels of 8–12 μg/L (by microparticle enzyme immunoassay [MEIA]).

For the low TAC–high SRL arm, 1 mg of SRL was given preoperatively. Postoperatively, SRL (5 mg/day) was started. The dose was adjusted to achieve levels of 8–12 ng/mL (by HPLC). TAC was started postoperatively at 0.03 mg/kg; the dose was adjusted to achieve levels of 3–7 μg/L. Of note, an SRL loading dose of 10 mg was used in both SRL groups until December 1, 2002; at that time, we stopped giving a loading dose (given reports from other centers that eliminating the loading dose decreased wound complications, and given our recognition that with Thymoglobulin induction a loading dose was likely unnecessary).

CMV prophylaxis consisted of IV ganciclovir during hospitalization, followed by oral ganciclovir or oral valganciclovir for 3 months. Pneumocystis prophylaxis was with Bactrim; in patients with sulfa allergies, dapsone or aerosolized pentamidine was used. Fungal prophylaxis was with oral clotrimazole or nystatin for 3 months posttransplant.

Recipients with ≥25% increase in their serum creatinine level underwent percutaneous allograft biopsy (histologic analysis and C4d study). Acute rejection episodes were treated with steroids or with primary antibody therapy. Steroid-resistant rejection episodes were treated with antibody. Recipients with acute rejection were maintained on prednisone (5 mg/day) long-term (although a few insisted on coming off prednisone again).

Data analysis

We studied patient and graft survival rates and the incidence and timing of acute rejection episodes. Each arm was analyzed as intention to treat. Graft failure was defined by a retransplant, by a return to dialysis, or by death with a functioning graft. We compared patient and graft survival rates and the incidence of rejection for the three arms. We also determined the incidence of a number of steroid- and immunosuppression-related side effects, including cataracts, fractures, avascular necrosis, skin cancer, posttransplant diabetes mellitus (PTDM), posttransplant lymphoproliferative disorder (PTLD), and cytomegalovirus (CMV) infection. In addition, we obtained serum creatinine, cholesterol, and triglyceride levels, and report these for all recipients (intention to treat) and for those recipients still receiving their study regimen. Finally, we looked at the rate of drug switches for each arm.

Recipient characteristics were compared using chi-squared tests (categorical variables) and Kruskal–Wallis tests (continuous variables). Actuarial rates for graft and patient survival, rejection, and posttransplant complications were estimated using Kaplan–Meier methods and compared using log-rank tests. Continuous measurements were compared using Kruskal–Wallis tests. Differences were labeled significant if the corresponding p-value was less than 0.05.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Of the 239 kidney transplants, 166 had living donors and 73 had deceased donors; 93% were first and 7% were second transplants; 97% were kidney alone and 3% were simultaneous kidney and pancreas. The mean recipient age was 49 ± 13 years. Recipient characteristics in each arm are shown in Table 1. We found no significant differences between arms.

Mean follow-up for the 239 recipients is 16 months; median, 15 months. We found no difference between arms in 2-year patient survival rates (Table 2). In all, 2 deaths occurred in the CSA–MMF arm (fungal sepsis, hyperkalemia); 3 in the high TAC–low SRL arm (cardiac dysfunction, hyperkalemia, GVHD); and 3 in the low TAC–high SRL arm (CVA, sepsis, respiratory failure).

Table 2.  Outcome posttransplant1
 6 months (%)12 months (%)24 months (%)
  1. 1p = NS for all comparisons between arms.

  2. NS = not significant.

Patient survival
 Low TAC–High SRL999797
 High TAC–Low SRL979797
Graft survival
 Low TAC–High SRL979696
 High TAC–Low SRL969494
Death-censored graft survival
 Low TAC–High SRL969999
 High TAC–Low SRL979797
Acute rejection-free graft survival
 Low TAC–High SRL989696
 High TAC–Low SRL979595
Chronic rejection-free graft survival
 Low TAC–High SRL989696
 High TAC–Low SRL1009898
 Dialysis first week748

We found no difference between arms in actuarial graft or death-censored graft survival rates (Table 2). Causes of graft loss included death with function (2 in each arm), technical reasons (1 CSA–MMF, 1 low TAC–high SRL), chronic rejection (2 CSA–MMF), primary nonfunction (1 low TAC–high SRL), recipient noncompliance (1 CSA–MMF), and calcineurin inhibitor toxicity (1 high TAC–low SRL). Of note, no graft losses occurred because of acute rejection in any of the arms.

We found no difference in either acute rejection-free or chronic rejection-free graft survival rates at 6, 12, or 24 months posttransplant (Table 2). Given an incidence of acute rejection of 5% at 6 months in the CSA–MMF arm, we have sufficient numbers enrolled, to date, in our study to not miss (power = 0.8) an incidence of >13.5% in the other arms. Similarly, at 12 months posttransplant, we have sufficient numbers enrolled to not miss (power = 0.8) an incidence of acute rejection >13.5%.

In the CSA–MMF arm, 6 recipients (7%) had an acute rejection episode: 3 mild, 2 moderate, and 1 severe. Of those 6 episodes, 4 were steroid-sensitive and 2 required primary antibody therapy. In the high TAC–low SRL arm, 4 recipients (5%) had an acute rejection episode: 3 mild and 1 moderate. Of those 4 episodes, 3 were steroid-sensitive and 1 required primary antibody therapy. In the low TAC–high SRL arm, 5 recipients (7%) had an acute rejection episode: 4 mild and 1 moderate. Of those 5 episodes, 2 were steroid-sensitive and 3 required primary antibody therapy.

Kidney function in all three arms was similar (Table 3). Of note, the serum creatinine level was slightly higher at 24 months posttransplant in the CSA–MMF arm (Table 3a). However, the differences were not statistically significant. Similarly, when only recipients still on original study drugs were analyzed, we found no differences (Table 3b).

Table 3.  Mean serum creatinine levels (ng/dL) (±SD)
a. Intention to treat
 6 months1.6 (0.5)1.7 (1.9)1.5 (0.5)
 12 months1.6 (0.6)1.5 (0.3)1.4 (0.4)
 24 months1.9 (1.6)1.6 (0.3)1.5 (0.3)
b. Recipients still on study regimen
 6 months1.5 (0.4)1.7 (0.2)1.5 (0.4)
 12 months1.6 (0.6)1.5 (0.4)1.4 (0.5)
 24 months1.6 (0.4)1.7 (0.3)1.5 (0.4)

We studied 12-month outcome for each arm by donor source and presence or absence of diabetes as the primary kidney disease (Table 4). Although the numbers in each subgroups are small, we found no difference between 16 randomized arms for living donor recipients, for deceased donor recipients, for diabetic recipients, or for nondiabetic recipients (Table 4).

Table 4.  Outcome posttransplant, by donor source and diabetic status
 % Survival at 12 months
Death-censored patient GraftAcute rejection-free
 High TAC10010088
 Low TAC9696100
 High TAC989498
 Low TAC989293
No type I diabetes
 High TAC989694
 Low TAC969496
Type I diabetes
 High TAC10094100
 Low TAC1009395

We looked at drug levels at 3 and 12 months posttransplant. The mean CSA level was 173 μg/L at 3 months and 135 μg/L at 12 months. In the high TAC arm, the mean TAC level was 9 μg/L at 3 months and 7.3 μg/L at 12 months. In the low TAC arm, the mean TAC level was 8.4 μg/L at 3 months and 7.0 μg/L at 12 months. In the low SRL arm, the mean SRL level was 6.7 μg/L at 3 months and 5.7 μg/L at 12 months. In the high SRL arm, the mean SRL level was 8.8 μg/L at 3 months and 8 μg/L at 12 months. The mean MMF dose was 1.76 at 3 months and 1.65 g/day at 12 months.

Drug-specific and immunosuppression-related complications occurred in each arm. Complications traditionally associated with prednisone therapy (cataracts, avascular necrosis, fractures) were rare. Overall, complication rates did not differ significantly (Table 5). However, wound complications (including nonhealing wound infections requiring the opening of at least part of the wound, and wound dehiscence) were more common in the SRL arms (especially the high SRL) (p = 0.02), as compared with the MMF arm. However, since eliminating the loading dose of SRL (December 1, 2002), SRL-treated recipients (although the numbers are small) no longer have significantly more wound complications. We noted no cases of polyomavirus infection. The only cases (n = 4) of PTDM were in the TAC–SRL arm. And 4 of 5 non-PTLD malignancies were in the CSA–MMF arm (Table 5).

Table 5.  Complications
  1. 1All within 6 months.

  2. CMV = cytomegalovirus, PTLD = posttransplant lymphoproliferative disorder, PTDM = posttransplant diabetes mellitus.

Other malignancies
CMV5 (6%)4 (5%)3 (4%) 
Wound complications (all)7 (8%)15 (18%)18 (25%)0.02
 Before December 1, 20026 (10%)12 (22%)13(28%)0.04
 After December 1, 20021 (5%)3 (11%)5 (20%)0.3
Mean weight gain at 1 year (kg)854NS

The lipid profile (intention to treat and those still on study regimen) and the use of lipid-lowering agents and antihypertensive agents for each arm are shown in Table 6. Even though 82% of high SRL–low TAC recipients were on lipid-lowering agents at 24 months posttransplant, we found no statistically significant differences between arms.

Table 6.  Laboratory values and medications
  1. p = NS for all comparisons in all arms.

Cholesterol (mg/dL) (±SD)
 a. Intention to treat
  Pretransplant171 (45)176 (42)175 (46)
  12 months167 (41)194 (66)184 (43)
  24 months173 (46)171 (35)188 (38)
 b. On treatment 
  Pretransplant175 (48)174 (39)175 (47)
  12 months168 (41)194 (59)184 (45)
  24 months175 (48)177 (31)196 (34)
Triglycerides (mg/dL) (±SD)
 a. Intention to treat
  Pretransplant166 (114)184 (119)180 (95)
  12 months201 (130)233 (192)204 (160)
  24 months133 (66)161 (80)211 (90)
 b. On treatment
  Pretransplant169 (125)178 (106)180 (90)
  12 months205 (127)246 (202)209 (167)
  24 months149 (62)167 (82)215 (94)
Antihypertensive agents
 Pretransplant (%)908691
 6 months (%)797888
 12 months (%)836773
Lipid-lowering agents
 Pretransplant (%)364348
 6 months (%)365948
 12 months (%)366944
 24 months (%)475782

Recipients in each arm switched drugs because of drug-specific complications. SRL was the drug most commonly switched; the most common reasons were wound healing concern or problem (22%), leukopenia (19%), mouth sores (8%), gastrointestinal intolerance (8%), DGF (6%), and hyperlipidemia (4%). TAC was switched because of hyperglycemia (16%), nephrotoxicity (16%), neurotoxicity (16%), and hair loss (8%). CSA was switched because of nephrotoxicity (23%), neurotoxicity (10%), and cosmetic changes (hirsutism and gingival hyperplasia) (10%).

In total, 198 (83%) of the 239 recipients remain prednisone-free. This includes 75% of the CSA–MMF group, 90% of the high TAC–low SRL group, and 83% of the low TAC–high SRL group.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Our study was designed to compare three maintenance immunosuppressive regimens for prednisone-free kidney recipients. All first and second kidney recipients at our institution were eligible for enrollment. The only exclusion criterion was taking maintenance prednisone within 3 months pretransplant; we felt such recipients represent a steroid withdrawal, rather than a steroid avoidance, regimen. As compared with previous multicenter, pharmaceutical company-originated studies in which we have participated, we were relatively flexible in our current study about dose reductions and drug switches.

At the outset, we realized that our study design would not allow us to determine whether or not any one drug was better than another; we would only be able to determine whether one combination was better than another. We had other potential choices for randomization. As discussed above, we could have randomized CSA–MMF (our maintenance therapy at the time we designed the study) vs. CSA–SRL. But, at the time we designed the study, there was concern that CSA–SRL was associated with increased 1-year graft dysfunction (vs. CSA protocols without SRL) (31,32). In retrospect, it appears that the increased graft dysfunction in those studies occurred because full doses of both drugs were used. We could have randomized CSA–MMF vs. TAC–MMF, but a major goal of our study was to determine whether or not SRL had any long-term advantages. In addition, most centers reporting a high incidence of posttransplant polyomavirus infection are using a TAC–MMF (with prednisone) combination. Historically, we have had a very low incidence of polyomavirus infection and did not want to create this problem for our recipients.

To date, we have found no differences in patient and graft survival rates or in the incidence of biopsy-proven acute rejection between our three arms (CSA–MMF, high TAC–low SRL, low TAC–high SRL). This alone is an important finding; it suggests that a variety of immunosuppressive regimens can be used successfully for prednisone-free maintenance immunosuppression. Other authors have also reported good short-term outcomes (without a high incidence of polyomavirus infection) using TAC–MMF. Moreover, we know from our previous studies that an acute rejection episode is a major risk factor for biopsy-proven chronic rejection (chronic allograft nephropathy) (33–35). Given that our current study's goal is to determine whether SRL (plus TAC) provides better long-term outcome vs. MMF (plus CSA), it is ideal that the incidence of acute rejection has, so far, not differed between our three arms.

We have also found no difference at this time between arms in some immunosuppression-related side effects (e.g. PTLD, CMV). In addition, in all arms the incidence of prednisone-related side effects (e.g. avascular necrosis, cataracts) was low. Wound complications were more common in the TAC–SRL arms (p = 0.02), but the incidence has decreased since we stopped giving an SRL loading dose. Of note, all 4 of our cases of PTDM occurred in the TAC–SRL arms (p = NS), but fewer malignancies occurred in the TAC–SRL arms (p = NS); this latter difference may be attributable to the reported anti-tumor effects of SRL (36).

More recipients in our TAC–SRL arms have switched drugs (usually to MMF) than recipients in the CSA–MMF arm. It should be noted that our standard regimen before this study was CSA–MMF, and we had not used SRL before this study; therefore, our transplant team probably had more comfort adjusting MMF doses (vs. SRL doses) for drug side effects.

Initial review of our data (n = 187) showed a clear difference in drug levels between our high TAC–low SRL and low TAC–high SRL arms (13). For both TAC and SRL, we had targeted 3–7 ng as a low level and 8–12 as a high level. As more recipients have enrolled, actual levels for those drugs are 9 ng/mL for high TAC, 8.4 for low TAC, 8.8 for high SRL, and 6.7 for low SRL; i.e. both of these arms are close to 8 ng/mL. Thus, it is not surprising that we are finding no differences between these two arms.

A separate question, not addressed in our current study, is whether prednisone-free immunosuppression itself is beneficial to kidney recipients. When asked, most recipients state that the immunosuppressive drug they would prefer to eliminate is prednisone (37). Almost all previous studies of prednisone-free immunosuppression either reported only the results of the prednisone-free group or compared the prednisone-free group with historical controls. In such studies, we and others showed that prednisone-free maintenance immunosuppression was associated with significantly fewer prednisone-related side effects, and not with an increased acute rejection rate. In addition, we previously reported 4-year follow-up results of a larger clinical series of rapid prednisone withdrawal (started before the current randomized study): we noted no increase in late graft loss for prednisone-free recipients (vs. historical controls) (22). Clearly, a large prospective study comparing prednisone vs. prednisone-free immunosuppression is needed to answer this question. Long-term follow-up will be necessary to ensure that steroid-free protocols are not associated with increased late posttransplant immunologic problems.

Another interesting question is why late withdrawal of prednisone is associated with an increased incidence of rejection (6–10), yet prednisone avoidance or rapid elimination is not (11–23). One possible explanation is that most prednisone avoidance trials use perioperative antibody. In fact, the European late prednisone withdrawal trial did not show an increased rejection rate in the subgroup receiving antibody induction (10). Also, perhaps important in our current study is that we gave the first antibody dose prevascularization. An alternative explanation might be that prednisone results in increased cytokine receptor expression on T cells, while simultaneously causing decreased cytokine release (38). Late withdrawal may result in cytokine release into an environment of upregulated receptors.

Germane, but not addressed in our study, is the role of prednisone-free maintenance immunosuppression vs. other possible maintenance regimens. We targeted reasonably low levels of calcineurin inhibitors (3–7 μg/L in the low TAC–high SRL arm; 8–12 μg/L in the high TAC–low SRL arm). But, our protocol does include long-term calcineurin inhibitor therapy. Others have suggested potential advantages to calcineurin inhibitor-sparing regimens, but most of those regimens have used prednisone. Ideally, with the introduction of new immunosuppressive agents, we will be able to create steroid- and calcineurin inhibitor-sparing regimens that have minimal side effects.

In summary, prednisone avoidance can be achieved in kidney recipients, with excellent short- and intermediate-term results. Each of the three immunosuppressive combinations we studied was associated with low acute rejection rates and excellent graft survival rates. Long-term follow-up is necessary to determine any differences between arms in graft dysfunction and late graft loss.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

We wish to thank Mary Knatterud for editorial assistance and Stephanie Daily for preparation of the manuscript. This work was supported by NIH Grant DK13083 and grants from Fujisawa and Genzyme (formerly SangStat).


  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  • 1
    Citterio F. Steroid side effects and their impact on transplantation outcome. Transplantation 2001; 72: S75S80.
  • 2
    Veenstra DL, Best JH, Hornberger J et al. Incidence and long-term cost of steroid-related side effects after renal transplantation. Am J Kidney Dis 1999; 33: 829839.
  • 3
    Fryer JP, Granger DK, Leventhal JR et al. Steroid-related complications in the cyclosporine era. Clin Transplant 1994; 8: 224229.
  • 4
    Schweizer RT, Rovelli M, Palmeri D et al. Noncompliance in organ transplant recipients. Transplantation 1990; 49: 374377.
  • 5
    Nevins TE, Kruse L, Skeans MA et al. The natural history of azathioprine compliance after renal transplantation. Kidney Int 2001; 60: 15651570.DOI: 10.1046/j.1523-1755.2001.00961.x
  • 6
    Sinclair NR. Low-dose steroid therapy in cyclosporine-treated renal transplant recipients with well-functioning grafts. The Canadian Multicentre Transplant Study Group. CMAJ 1992; 147: 645657.
  • 7
    Hricik DE, O'Toole MA, Schulak JA et al. Steroid-free immunosuppression in cyclosporine-treated renal transplant recipients: a meta-analysis. J Am Soc Nephrol 1993; 4: 13001305.
  • 8
    Kasiske BL, Chakkera HA, Louis TA et al. A meta-analysis of immunosuppression withdrawal trials in renal transplantation. Am Soc Nephrol 2000; 11: 19101917.
  • 9
    Ahsan N, Hricik D, Matas A et al. Prednisone withdrawal in kidney transplant recipients on cyclosporine and mycophenolate mofetil—a prospective randomized study. Steroid Withdrawal Study Group. Transplantation 1999; 68: 18651874.
  • 10
    Vanrenterghem Y, Lebranchu Y, Hene R et al. Double-blind comparison of two corticosteroid regimens plus mycophenolate mofetil and cyclosporine for prevention of acute renal allograft rejection. Transplantation 2000; 70: 13521359.DOI: 10.1097/00007890-200011150-00015
  • 11
    Birkeland SA. Steroid-free immunosuppression in renal transplantation: a long-term follow-up of 100 consecutive patients. Transplantation 2001; 71: 10891090.
  • 12
    Matas AJ, Ramcharan T, Paraskevas S et al. Rapid discontinuation of steroids in living donor kidney transplantation: a pilot study. Am J Transplant 2001; 1: 278283.DOI: 10.1034/j.1600-6143.2001.001003278.x
  • 13
    Kandaswamy R, Humar A, Khwaja K et al. A prospective, randomized study of cyclosporine/CellCept vs. tacrolimus/sirolimus with rapid discontinuation of prednisone (abstract). Am J Transplant 2003; 3: 198.
  • 14
    Kaufman DB, Leventhal JR, Fryer JP et al. Kidney transplantation without prednisone (abstract). Transplantation 2000; 69: S133.
  • 15
    Vincenti F, Monaco A, Grinyo J et al. Multicenter randomized prospective trial of steroid withdrawal in renal transplant recipients receiving basiliximab, cyclosporine microemulsion and mycophenolate mofetil. Am J Transplant 2003; 3: 306311.DOI: 10.1034/j.1600-6143.2003.00005.x
  • 16
    Leventhal JR, Kaufman DB, Lorenzo G et al. Four-year single center experience with prednisone-free immunosuppression in 434 kidney transplant recipients (abstract). Am J Transplant 2003; 3: 439.DOI: 10.1034/j.1600-6143.2003.00059.x
  • 17
    Cole E, Landsberg D, Russell D et al. A pilot study of steroid-free immunosuppression in the prevention of acute rejection in renal allograft recipients. Transplantation 2001; 72: 845850.
  • 18
    Sarwal MM, Yorgin PD, Alexander S et al. Promising early outcomes with a novel, complete steroid avoidance immunosuppression protocol in pediatric renal transplantation. Transplantation 2001; 72: 1321.DOI: 10.1097/00007890-200107150-00006
  • 19
    Boots JM, Christiaans MH, Van Duijnhoven EM, Van Suylen RJ, Van Hooff JP. Early steroid withdrawal in renal transplantation with tacrolimus dual therapy: a pilot study. Transplantation 2002; 74: 17031709.
  • 20
    Calne R, Moffatt SD, Friend PJ, Jamieson NV, Bradley JA, Hale G. Campath IH allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients. Transplantation 1999; 68: 16131616.
  • 21
    Khwaja K, Asolati M, Harmon J et al. Outcome at 3 years with a prednisone-free maintenance regimen: a single-center experience with 349 kidney transplant recipients. Am J Transplant 2004; 4: 980987.DOI: 10.1111/j.1600-6143.2004.00443.x
  • 22
    Matas AJ, Kandaswamy R, Humar A et al. Long-term immunosuppression, without maintenance prednisone, after kidney transplantation. Ann Surg 2004; 240: 510517.
  • 23
    Sarwal MM, Vidhun JR, Alexander SR et al. Continued superior outcomes with modification and lengthened follow-up of a steroid-avoidance pilot with extended dacluzimab induction in pediatric renal transplantation. Transplantation 2003; 76: 13311339.DOI: 10.1097/01.TP.0000092950.54184.67
  • 24
    Sousa JE, Costa MA, Abizaid A et al. Lack of neointimal proliferation after implantation of sirolimus-coated stents in human coronary arteries. A quantitative coronary angiography and three-dimensional intravascular ultrasound study. Circulation 2001; 103: 192195.
  • 25
    Luo Y, Marx SO, Kiyokawa H, Koff A, Massague J, Marks AR. Rapamycin resistance tied to defective regulation of p27Kip1. Mol Cell Biol 1996; 16: 67446751.
  • 26
    Poon M, Marx SO, Gallo R, Badimon JJ, Taubman MB, Marks AR. Rapamycin inhibits vascular smooth muscle cell migration. J Clin Invest 1996; 98: 22772283.
  • 27
    Gregory CR, Huang X, Pratt RE et al. Treatment with rapamycin and mycophenolic acid reduces arterial intimal thickening produced by mechanical injury and allows endothelial replacement. Transplantation 1995; 59: 655661.
  • 28
    Burke SE, Lubbers NL, Chen YW et al. Neointimal formation after balloon-induced vascular injury in Yucatan minipigs is reduced by oral rapamycin. J Cardiovasc Pharmacol 1999; 33: 829835.
  • 29
    Gallo R, Padurean A, Jayaraman T et al. Inhibition of intimal thickening after balloon angioplasty in porcine coronary arteries by targeting regulators of the cell cycle. Circulation 1999; 99: 21642170.
  • 30
    Morice MC, Serruys PW, Sousa JE et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002; 346: 17731780.DOI: 10.1056/NEJMoa012843
  • 31
    Kahan BD. Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study. The Rapamune US Study Group. Lancet 2000; 356: 194202.DOI: 10.1016/S0140-6736(00)02480-6
  • 32
    MacDonald AS. RAPAMUNE Global Study Group. A worldwide, phase III, randomized, controlled, safety and efficacy study of a sirolimus/cyclosporine regimen for prevention of acute rejection in recipients of primary mismatched renal allografts. Transplantation 2001; 71: 271280.DOI: 10.1097/00007890-200101270-00019
  • 33
    Basadonna GP, Matas AJ, Gillingham KJ et al. Early vs. late acute rejection: impact on chronic rejection. Transplantation 1993; 55: 993995.
  • 34
    Almond PS, Matas AJ, Gillingham KJ et al. Risk factors for chronic rejection in renal allograft recipients. Transplantation 1993; 55: 732737.
  • 35
    Humar A, Hassoun A, Kandaswamy R et al. Immunologic factors: the major risk for decreased long-term graft survival. Transplantation 1999; 68: 18411846.
  • 36
    Mita MM, Mita A, Rowinsky EK. The molecular target of rapamycin (mTOR) as a therapeutic target against cancer. Cancer Biol Ther 2003; 2: S169S177.
  • 37
    Prasad GV, Nash MM, McFarlane PA, Zaltzman JS. Renal transplant recipient attitudes toward steroid use and steroid withdrawal. Clin Transplant 2003; 17: 135139.DOI: 10.1034/j.1399-0012.2003.00034.x
  • 38
    Almawi WY, Melemedjian OK, Rieder MJ. An alternate mechanism of glucocorticoid anti-proliferative effect: promotion of a Th2 cytokine-secreting profile. Clin Transplant 1999; 13: 365374.DOI: 10.1034/j.1399-0012.1999.130501.x